This proposal describes experiments designed to elucidate the mechanism by which the nervous system regulates innate immunity in response to pathogen infection. Our work in Caenorhabditis elegans has led to the identification of mutants that exhibit aberrant responses when infected with different pathogens. Analysis of these C. elegans mutants deficient in immune responses is clarifying the roles of a variety of interacting and intersecting genetic pathways involved in immune responses highly conserved across species, including humans. The latest studies from our laboratory indicate that innate immunity in C. elegans is regulated by neurons expressing NPR- 1, which is a G-protein-coupled receptor related to mammalian neuropeptide Y receptors. Our studies have demonstrated that a neural circuit involving NPR-1 functions to suppress innate immune responses. The immune inhibitory function requires a cyclic GMp-gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we showed that npr-1- and gcy- 35expressing sensory neurons actively suppress immune responses of non-neuronal tissues. A full-genome microarray analysis on animals with altered neural function due to mutation in npr-1 showed an enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-11p38 mitogen-activated protein kinase signaling pathway. This proposal will continue our studies utilizing a C. elegans model to clarify the role of the nervous system in the regulation of innate immunity against bacterial pathogens. We hypothesize that G- protein coupled receptors (GPCRs) may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate innate immune responses. There are two specific aims: 1) Study of the immune function of C. elegans mutants in neuronal GPCR-encoding genes. 2) Study the effect of pathogen exposure on neural responses.